The present invention relates to a process for producing dicarboxylic acid monoesters by transesterification of a dicarboxylic acid monoester which are useful as intermediates for medicines and agricultural chemicals, main starting materials for polyester polyols, nylons, fibers, lubricants, plasticizers, etc., or additives thereto or precursors thereof, especially useful as starting materials for synthesis of asymmetrical diesters of dicarboxylic acids.
Transesterifications using catalysts containing tin, titanium, etc. are well known, but these catalysts are deactivated if acids are present in the reaction systems. Therefore, these catalysts cannot be used for substrates containing carboxylic acid in the structure, such as dicarboxylic acid monoesters.
Under the circumstances, many processes for the production of dicarboxylic acid monoesters have been proposed, and these are roughly classified into the following five processes.
(a) Monoesterification of dicarboxylic acids:
Fiziol. Akt. Veshchestva, 7, 129-31(1975).
J. Chem. Res. Synopses, (5), 119(1977). JP-A-4-112854
(b) Decomposition of dicarboxylic acid diesters:
Tetrahedron Lett., 32(34), 4239-42(1991).
Chem. Lett., (7), 539-40(1995).
(c) Ring opening of cyclic dicarboxylic acid anhydrides with alcohols or metal alkoxides:
Synlet, 6, 650-2(1995).
(d) Condensation reaction:
J. Org. Chem., 33(2), 838-40(1968).
Tetrahedron Lett., (32), 2721-3(1974).
J. Organomet. Chem., 364(3), C29-32(1989).
(e) Synthesis of malonic monoesters from Meldrum""s acid:
Tetrahedron Lett., 30(23), 3073-6(1989).
However, these processes (a)-(e) all have the following problems.
In the process (a), both the two carboxyl groups are esterified to produce diesters as by-products, and in the process (b), both the ester groups are hydrolyzed to produce dicarboxylic acids as by-products. Therefore, according to these processes, it is difficult to obtain monoesters with a high selectivity, and thus it is difficult to industrially efficiently obtain the desired monoesters. In the process (c), the reaction is carried out under a high pressure and special pressure reaction vessels such as autoclave are needed, resulting in increase of production cost. Moreover, according to this process, two kinds of monoesters are produced at the same time, and, hence, it is difficult to obtain selectively a monoester with a carboxyl group of the desired position being monoesterified. Furthermore, according to this process, when optically active monoesters are obtained using optically active cyclic dicarboxylic acid anhydrides as a starting material, there is the possibility that optical purity of the monoesters greatly decreases. In the case of the processes (d) and (e), the kinds of dicarboxylic acid monoesters which can be synthesized are limited and it is difficult to apply these processes to the production of a wide variety of dicarboxylic acid monoesters.
For these reasons, a process for industrially producing a wide variety of dicarboxylic acid monoesters at a high selectivity has been desired. Moreover, a process for producing dicarboxylic acid monoesters using optically active starting materials without causing a great reduction in optical purity has also been desired.
In general, transesterification between esters and metal alkoxides is known. However, when a dicarboxylic acid monoester as a starting material for esters and a metal alkoxide are subjected to transesterification in an organic solvent, production of a metal salt of the dicarboxylic acid monoester takes place in preference to transesterification, and since the resulting metal salt is hardly soluble in the organic solvent, it is considered that the desired transesterification hardly proceeds. There is no report on actually performing such reaction.
The present inventors have found that contrary to the above conventional common knowledge, even if a metal salt of dicarboxylic acid monoester represented by the formula (1) is produced in the reaction system, the transesterification satisfactorily proceeds by selecting the reaction conditions.
The object of the present invention is to provide a process for producing dicarboxylic acid monoesters according to which a wide variety of dicarboxylic acid monoesters can be obtained at a high selectivity by substituting a desired alkoxy group for an alkoxy group of the ester moiety of dicarboxylic acid monoesters which can be synthesized by known processes, and, furthermore, and optically active dicarboxylic acid monoesters can be produced from optically active starting materials with less deterioration of optical purity.
As a result of an intensive research conducted by the present inventors in an attempt to attain the above object, it has been found that a wide variety of dicarboxylic acid monoesters can be obtained at a high selectivity by subjecting an alcohol and a dicarboxylic acid monoester or an alkali salt of a dicarboxylic acid monoester to transesterification in the presence of a metal alkoxide or by subjecting a metal alkoxide and a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester to transesterification in the presence of an organic solvent. Thus, the present invention has been accomplished.
That is, the present invention relates to a process for producing a dicarboxylic acid monoester represented by the formula (3) which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester represented by the formula (1) as a starting material and a metal alkoxide represented by the formula (2) to transesterification in the presence of an organic solvent:
R1OOCxe2x80x94(CH2)mxe2x80x94Xxe2x80x94(CH2)nxe2x80x94COOM1xe2x80x83xe2x80x83(1)
wherein R1 represents a straight-chain or branched-chain alkyl group, alkoxyalkyl group or alkylthioalkyl group of 1-18 carbon atoms, of which one or more hydrogen atoms may be substituted with phenyl group, naphthyl group, toluyl group or fluorine atom, m and n each represent an integer of 0-12 (m+nxe2x89xa618), X represents a group represented by one of the formula (X1) to the formula (X5), and M1 represents a hydrogen atom or an alkali metal, 
in which Z1 and Z2 each represent a hydrogen atom, a fluorine atom, a phenyl group, a naphthyl group or a straight-chain or branched-chain alkyl group or alkenyl group of 1-12 carbon atoms, 
in which Z3, Z4, Z5 and Z6 each represent a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, 
in which Z1 and Z2 are as defined in the formula (X1), 
in which Z1 and Z2 are as defined in the formula (X1), 
in which Z1 and Z2 are as defined in the formula (X1);
R2OM2xe2x80x83xe2x80x83(2)
wherein R2 represents a straight-chain or branched-chain alkyl group, alkoxyalkyl group or alkylthioalkyl group of 1-18 carbon atoms, of which one or more hydrogen atoms may be substituted with phenyl group, naphthyl group, toluyl group or fluorine atom, and M2 represents an alkali metal]; and
R2OOCxe2x80x94(CH2)mxe2x80x94Xxe2x80x94(CH2)nxe2x80x94COOM1xe2x80x83xe2x80x83(3)
wherein R2 is as defined in the formula (2), and m, n, X and M1 are as defined in the formula (1).
Furthermore, the present invention relates to a process for producing a dicarboxylic acid monoester represented by the formula (5) which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester represented by the formula (1) as a starting material and an alcohol represented by the formula (4) to transesterification in the presence of a metal alkoxide represented by the above formula (2):
R3OHxe2x80x83xe2x80x83(4)
wherein R3 represents a straight-chain or branched-chain alkyl group, alkoxyalkyl group or alkylthioalkyl group of 1-18 carbon atoms, of which one or more hydrogen atoms may be substituted with phenyl group, naphthyl group, toluyl group or fluorine atom; and
R3OOCxe2x80x94(CH2)mxe2x80x94Xxe2x80x94(CH2)nxe2x80x94COOM1xe2x80x83xe2x80x83(5)
wherein R3 is as defined in the formula (4), and m, n, X and M1 are as defined in the formula (1)
The dicarboxylic acid monoesters or alkali metal salts of the dicarboxylic acid monoesters used as a starting material in the present invention are not limited as far as they are represented by the formula (1), and they may be those which are commercially available or synthesized by known processes. As these dicarboxylic acid monoesters or alkali metal salts of the dicarboxylic acid monoesters (hereinafter referred to as xe2x80x9cstarting monoestersxe2x80x9d), mention may be made of, for example, monoesters of adipic acid, terephthalic acid, malonic acid, methylsuccinic acid, succinic acid, itaconic acid, citraconic acid, glutaric acid and the like, or metal salts of these monoesters. The metals which form the metal salts here are not limited as far as they are alkali metals, but potassium and sodium are preferred, and potassium is especially preferred because the salts formed are superior in solubility. Moreover, the starting monoesters may be optical active compounds.
The metal alkoxides used as a starting material of the transesterification in place of alcohol are not limited as far as they are represented by the formula (2), but potassium alkoxides are especially preferred because they are superior in solubility. The kind of the alkoxy group of the metal alkoxides depends on the desired dicarboxylic acid monoesters and is not particularly limited. Preferred are methoxy group, ethoxy group, n-propoxy group, n-butoxy group and tert-butoxy group. When the metal alkoxide is used as a starting material of the transesterification, the amount of the metal alkoxide may be 1.01 mol or more per mol of the starting dicarboxylic acid monoester (hereinafter sometimes referred to as xe2x80x9cstarting monoesterxe2x80x9d), and preferably 1.01-3 mols per mol of the starting mono-esters taking the cost into consideration. If the amount of the metal alkoxide is less than 1 mol per mol of the starting monoesters, an acid-base reaction takes place preferentially and this is not preferred.
The metal alkoxides to be allowed to exist in the reaction system when alcohol is used as a starting material of the transesterification in place of metal alkoxide are not limited as far as they are represented by the formula (2), but potassium alkoxides are especially preferred because they are superior in solubility. The kind of the alkoxy group of the metal alkoxides is not limited, but preferred are methoxy group, ethoxy group, n-propoxy group, n-butoxy group and tert-butoxy group. However, if the alkoxy group of the starting alcohol is different from that of the metal alkoxide, undesired esters are partially produced, and, hence, it is preferred to use a metal alkoxide having the same alkoxy group as of the alcohol represented by the formula (4) used in the reaction. When the metal alkoxide is used as a catalyst for the transesterification as mentioned above, the amount of the metal alkoxide may be 1.01 mol or more per mol of the starting monoester in the case of the starting monoesters being dicarboxylic acid monoester, and preferably 1.01-3 mols per mol of the starting monoester taking the cost into consideration. In the case of the starting monoesters being the alkali metal salt, the amount of the metal alkoxide may be 0.01 mol or more per mol of the starting monoester, and preferably 0.01-2 mols per mol of the starting monoester taking the cost into consideration.
The alcohols used as a starting material in the present invention are not limited as far as they are represented by the formula (4). Examples of these alcohols (hereinafter referred to as xe2x80x9cstarting alcoholsxe2x80x9d) include straight-chain aliphatic alcohols such as methanol, ethanol, n-propyl alcohol and n-butyl alcohol, branched aliphatic alcohols such as isopropyl alcohol, isobutyl alcohol and tert-butyl alcohol, unsaturated aliphatic alcohols such as allyl alcohol and methallyl alcohol, alcohols containing aromatic group such as benzyl alcohol, 4-nitrobenzyl alcohol, 3,5-dinitrobenzyl alcohol and phenethyl alcohol, and cellosolve alcohols such as ethylene glycol monomethyl ether and diethylene glycol monomethyl ether.
The amount of the starting alcohol used is preferably 1-200 mols, especially preferably 5-50 mols per mol of the starting monoesters. When the starting monoesters are an alkali metal salt, it is preferred to use the starting alcohol in a greatly excess amount over the amount of the alkali metal salt of the starting monoester for the purposes of improving the solubility of the alkali metal salt as the starting monoester, shortening the reaction time and improving the conversion in the transesterification. However, in case the starting alcohol has a high boiling point and is difficult to remove by distillation after completion of the reaction or the amount of the starting alcohol should be decreased because of its high price, use of the starting alcohol in a slightly excess amount per mol of the starting monoesters can fully attain the purposes.
When an alcohol is used as a starting material and a metal alkoxide is used as a catalyst, the order of mixing of the starting materials before subjected to the reaction is not particularly limited, and, for example, there are the following methods: a method of mixing the starting monoesters with the alcohol which is another starting material and thereafter adding the metal alkoxide (method A); a method of mixing the starting alcohol with the metal alkoxide and thereafter adding the starting monoesters (method B); a method of mixing the starting monoesters with the metal alkoxide and thereafter adding the starting alcohol (method C); a method of mixing the starting monoesters with an organic solvent and an additive and thereafter adding the metal alkoxide (method D); a method of mixing the metal alkoxide with an organic solvent and an additive and thereafter adding the starting monoesters (method E); etc. The order of mixing according to methods A, B, D and E are preferred from the point of operability.
When the starting monoesters are optical active compounds having an asymmetric center at xcex1-position, there is the possibility of xcex1-hydrogen of the is ester being drawn by the metal alkoxide. Therefore, in order to maintain a high optical purity of the product, it is preferred to add the metal alkoxide lastly as in the method A or D.
When a starting alcohol is used in the present invention, the solvent and the additive are not necessarily needed, but they may be used for the acceleration of the reaction. When the starting alcohol is not used, a solvent is necessarily used and an additives) can be optionally added.
The solvents usable include organic solvents, for example, aromatic hydrocarbon solvents such as benzene, nitrobenzene, toluene and xylene, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,3-dioxolan and 1,4-dioxane, carbon disulfide, nitromethane, N,N-dimethylformamide, and dimethyl sulfoxide.
The additives are preferably those which activate the carbonyl group of the metal alkoxide or ester, those which have an effect of increasing the solubility of the metal alkoxide or the starting monoesters or those which have an effect as a phase-transfer catalyst. Examples of the additives include amines such as triethylamine and tetramethylenediamine, nitrogen-containing aromatic compounds such as pyridine, quaternary ammonium salts such as benzyltriethylammonium chloride and tetra-n-butylammonium bromide, crown ethers such as 18-crown-6, and compounds having an inclusion effect similar to that of the crown ethers, such as tetrahydrofuran, 1,2-dimethoxyethane, 1,3-dioxolan and 1,4-dioxane.
Reaction temperature of the transesterification can be optionally set usually in a range of xe2x88x92100 to 250xc2x0 C., preferably xe2x88x9280 to 200xc2x0 C., more preferably xe2x88x9220 to 150xc2x0 C. Since the reaction of the present invention is an equilibrium reaction, in order to improve the reaction rate and the conversion, it is preferred to carry out the reaction while alcohol (R1OH) produced from the starting monoesters by transesterification is removed out of the reaction system by evaporation, etc. Therefore, the reaction temperature is preferably not less than the boiling point or azeotropic point of the alcohol (R1OH) produced by the transesterification. In case the alcohol resulting from the metal alkoxide used as a starting material or the starting alcohol is also simultaneously distilled off by evaporation, this alcohol or a solution containing this alcohol may be added to the reaction system.
The pressure during the transesterification can be optionally set usually in a range of 1 kPa-5 MPa (absolute pressure). Practically, 10 kPa-1 MPa (absolute pressure) is preferred, and 80-120 kPa (absolute pressure) is more preferred. The reaction time of the transesterification can be optionally set usually in a range of 0.01-100 hours, and 0.1-50 hours is preferred considering the efficiency of reaction vessel.